The present invention is related to the area of chemical synthesis. More specifically, one embodiment of the present invention provides methods for the solid phase and combinatorial synthesis of 4-thiazolidinones, metathiazanones and derivatives thereof.
Obtaining a better understanding of the important factors in molecular recognition in conjunction with developing potent new therapeutic agents is a major focus of scientific research. Chemical and biological methods have recently been developed for the generation of large combinatorial libraries of peptides and oligonucleotides that are then screened against a specific receptor or enzyme in order to determine the key molecular recognition elements of the biopolymer for that receptor or enzyme. See U.S. Pat. No. 5,143,854; Ser. No. 07/805,727, filed Dec. 6, 1991, now U.S. Pat. No. 5,424,186; Ser. No. 07/624,120, filed Dec. 6, 1990, now abandoned; Ser. No. 07/946,239, filed Sep. 16, 1992, still pending; Ser. No. 07/762,522, filed Sep. 18, 1991, now abandoned; Ser. No. 07/978,940, filed Nov. 19, 1992, now abandoned; and Ser. No. 07/971,181, filed Nov. 2, 1992, now abandoned; each of which is assigned to the assignee of the present invention and incorporated herein by reference for all purposes. These methods provide rapid and efficient means to synthesize polymers that are biocompatible, i.e., compounds that are non-toxic and readily absorbed, and ideally are synthesized from monomers available in large quantity, with a reasonable shelf life, optical activity, high-fidelity coupling chemistry, and stable to various chemical reagents used for protecting and deprotecting various side chains.
Virtually any bioavailable organic compound can be accessed by chemical synthesis; however, such compounds typically are still synthesized and evaluated one at a time in many cases, thus dramatically limiting the number of derivatives which can be studied. This limitation can be overcome by developing the methodology for the combinatorial synthesis of large numbers of derivatives of therapeutically important classes of bioavailable organic compounds. Screening these compounds against key receptors or enzymes would then greatly accelerate the acquisition of useful structure versus recognition data and would revolutionize the search for potent new therapeutic agents.
The search for suitable small organic molecules amenable to a combinatorial synthesis approach is an ongoing quest. One ideal goal is to tailor the chemistry used to assemble the molecules to work in a polymer-supported fashion, in analogy to solid phase techniques commonly employed for peptides and oligonucleotides. The advantages of such a goal is twofold: not only does one gain overall efficiency through the ability to filter away both byproducts and excess reagents, but one also raises the possibility of mass screening of the immobilized molecules with techniques such as VLSIPS.TM. and ESL technologies. See, U.S. Pat. No. 5,143,854; Ser. No. 07/805,727, filed Dec. 6, 1991, U.S. Pat. No. 5,424,186; Ser. No. 07/624,120, filed Dec. 6, 1990, now abandoned; Ser. No. 07/946,239, filed Sep. 16, 1992, still pending; and Ser. No. 07/762,522, filed Sep. 18, 1991, now abandoned; each of which is assigned to the assignee of the present invention and incorporated herein by reference for all purposes.
Perhaps the first example of the application of combinatorial organic synthesis to non-polymeric organic compounds can be found in the work of Ellman who described the solid phase synthesis of a 1,4-benzodiazepines. See U.S. Pat. No. 5,288,514, which is incorporated herein by reference for all purposes. The benzodiazepines were synthesized on a solid support by the connection of three building blocks: an amino benzophenone; an amino acid; and an alkylating agent.
Hobbs Dewitt has reported on the generation of libraries of small molecules, which she terms "diversomers". Target compounds, including dipeptides, hydantoins, and benzodiazepenes, were synthesized simultaneously but separately, on a solid support in an array format, to generate a collection of up to 40 discrete structurally related compounds. The key step in this strategy involves the revealing of distal functionality which initiates attack on the bond linking the compound to the resin, thus, releasing the product from the resin.
In addition to the small organic molecules discussed above, another important class of molecules is the 4-thiazolidinones (herein referred to as thiazolidinones), metathiazanones, and derivatives thereof. The generic structure and numbering system of these compounds is shown below: ##STR1##
Substituted 4-thiazolidinones possess many properties important for biological activity, such as optical activity and the ability to form hydrogen bonds and to carry side chain functionalities. Thiazolidinones have been shown to exhibit antifungal (see, e.g., Srivastava et al. (1991) Ind. J. Chem. 30:620-623; and Abdel-Rahman et al. (1990) J. Ind. Chem. Soc. 67:61-64); antihistaminic (see, e.g., Diurno et al. (1992) J. Med. Chem. 35:2910-1912); anti-platelet aggregation factor (see, e.g., Tanabe et al. (1991) Tetrahedron Lett. 32:379-382; and Tanabe et al. (1991) Tetrahedron Lett. 32:383-386); and antimicrobial (see, e.g., Hogale et al. (1991) Ind. J. Chem. 306:717-720) activities. In addition, this class of compounds has found use in the treatment of inflammation, hypertension, renal failure, congestive heart failure, uremia and other conditions. See, e.g., Walsh and Uwaydah, U.S. Pat. Nos. 5,061,720 and 4,225,609. 4-Thiazolidinones are therefore prime candidates for drug studies.
4-Thiazolidinones have been synthesized via the condensation of an aldehyde, an amine and a mercaptoacetic acid to generate the five-membered ring with the concomitant loss of two molecules of water. See, e.g., Diurno et al. (1992) J. Med. Chem. 35:2910-1912; Surrey and Cutler (1954) J. Am. Chem. Soc. 76: 578-580; and El-Kohry (1992) OPPI Briefs 24:81-83. The most likely mechanism for this condensation involves initial imine formation between the aldehyde and the amine, followed by addition of the thiol to the carbon-nitrogen double bond and finally ring closure. Treatment of an imine with a mercaptoacetic acid also generates a thiazolidinone in high yield. See Srivastava et al. supra; Abdel-Rahman et al. supra; and Tanabe et al. supra. The synthesis of metathiazanones proceeds through the analogous reaction of an amine, aldehyde, and .beta.-mercaptopropionic acid.
Unfortunately, there has been a lack of efficient techniques for synthesizing immobilized 4-thiazolidinones and particularly, for producing arrays of 4-thiazolidinones. The present invention meets this need.